Sex-specific associations of Notch signaling with chronic HBV infection: a study from Taiwan Biobank.

BACKGROUND: Hepatitis B, a liver infection caused by the hepatitis B virus (HBV), can develop into a chronic infection that puts patients at high risk of death from cirrhosis and liver cancer. In this study, we aimed to investigate the difference of reactome pre-Notch expression and processing between males and females by using gene to function analysis in FUMA. METHODS: We analyzed Taiwan Biobank (TWB) data pertaining to 48,874 women and 23,178 men individuals which were collected from 2008 to 2019. According to hepatitis B surface antigen (HBsAg) status in hematology, positive and negative were classified into case and control in the genome-wide association study (GWAS) analysis. RESULTS: We found 4715 women and 2656 men HBV cases. The genomic risk loci were different between males and females. In male, three risk loci (rs3732421, rs1884575 and Affx-28516147) were detected while eight risk loci (Affx-4564106, rs932745, rs7574865, rs34050244, rs77041685, rs107822, rs2296651 and rs12599402) were found in female. In addition, sex also presented different results. In females, the most significant SNPs are gathered in chromosome 6. However, except for chromosome 6, significant HBV infection SNPs also could be found in chromosome 3 among males. We further investigated gene function in FUMA to identify the difference in reactome pre-Notch expression and processing between males and females. We found that POGLUT1 and HIST1H2BC only appeared in men but not in women. CONCLUSION: According to our study, the reactome pre-Notch expression including POGLUT1 and HIST1H2BC was associated with a risk of Hepatitis B in Taiwanese men when compared to women.

Hepatitis B is a serious liver infection caused by the hepatitis B virus (HBV). It can lead to long-term liver damage and cancer. We looked at differences in how the virus affects men and women in Taiwan. We analyzed data from over 72,000 people in the Taiwan Biobank. The study individuals were divided into two groups­those who had the hepatitis B virus (cases) and those who did not (controls). We looked for genetic differences between the two groups and found that the specific genetic risk factors for hepatitis B differed between men and women. We found three genetic risk factors in men and eight in women. This suggests that the way the hepatitis B virus interacts with our genes may differ between the sexes. We found that in women, the most significant genetic risk factors were all located on chromosome 6. However, in men, the significant risk factors were spread across different chromosomes, including chromosome 3. Finally, we looked at how these genetic differences might affect the way the body processes the hepatitis B virus. We found that two specific genes, called POGLUT1 and HIST1H2BC, were only linked to hepatitis B risk in men, not in women. This indicates that the biological pathways involved in hepatitis B infection may differ between males and females. Understanding these differences could lead to more effective, personalized treatment strategies for those affected by the virus.

Didymin ameliorates ulcerative colitis-associated secondary liver damage by facilitating Notch1 degradation.

BACKGROUND: Didymin is a dietary flavonoid originally discovered by our group as a potent anti-ulcerative colitis (UC) agent. However, whether didymin plays a protective role in UC-associated inflammatory liver injury is still unclear. PURPOSE: This study aimed to evaluate the therapeutic potential of didymin on UC-associated inflammatory liver injury and explore the underlying mechanism. STUDY DESIGN AND METHODS: Colitis model was established in C57BL/6 mice by exposure to DSS, and didymin was administrated intragastrically for consecutive 10 days. The inflammatory liver injury was assessed by levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum and histopathological damage in the liver. In vitro Kupffer cells and RAW264.7 cells challenged with lipopolysaccharides (LPS) were used to explore the modulatory activity of didymin on pro-inflammatory cytokines secretion and Notch1 signaling pathway activation. RESULTS: Didymin significantly mitigated liver coefficiency, ALT and AST levels in serum, and the hepatic histopathological damage caused by DSS-induced acute and chronic colitis. The mRNA expressions of pro-inflammatory factors including Tnf, Il1, and Il6 in liver tissues, Kupffer cells, and RAW264.7 cells stimulated by the influx of LPS was significantly deprived after didymin treatment. Mechanistically, didymin obstructed the protein expression, nuclear translocation of notch intracellular domain 1 (Notch1-ICD) and mRNA expression of hairy and enhancer of split 1 (Hes1). Further, the inhibitory mechanism of the Notch1-Hes1 pathway was dependent on c-Cbl-mediated Notch1-ICD lysosomal degradation. CONCLUSION: Our study verified for the first time that didymin could prevent UC-associated diseases, such as inflammatory liver injury, and the mechanism was related to facilitating Notch1 lysosomal degradation rather than proteasome degradation via promoting protein expression of c-Cbl in macrophages. Our findings that the inhibition of Notch1 signaling transduction helps to alleviate UC-associated liver injury provides possible therapeutics for the treatment of colitis and also furnishes a research paradigm for the study of flavonoids with similar structures.

Airineme-Mediated Intercellular Communication.

Intercellular communication is indispensable across multicellular organisms, and any aberration in this process can give rise to significant anomalies in developmental and homeostatic processes. Thus, a comprehensive understanding of its mechanisms is imperative for addressing human health-related concerns. Recent advances have expanded our understanding of intercellular communication by elucidating additional signaling modalities alongside established mechanisms. Notably, cellular protrusion-mediated long-range communication, characterized by physical contact through thin and elongated cellular protrusions between cells involved in signal transmission and reception, has emerged as a significant intercellular signaling paradigm. This chapter delves into the exploration of a signaling cellular protrusion termed 'airinemes,' discovered in the zebrafish skin. It covers their identified signaling roles and the cellular and molecular mechanisms that underpin their functionality.

Surgical Debulking Modifies Notch Signaling and May Improve Vismodegib Effectiveness for Locally Advanced Basal Cell Carcinoma.

Smoothened inhibitors, such as vismodegib, exhibit remarkable success in treating patients with locally advanced basal cell carcinoma (LaBCC). Yet, vismodegib efficacy is hindered by notable side effects, which often lead to treatment discontinuation and subsequent relapse in patients with LaBCC. Prolonged remission was previously reported in patients with LaBCCs who underwent surgical debulking before starting vismodegib. In this study, we enrolled 4 patients with LaBCC who underwent debulking followed by vismodegib therapy to assess their clinical outcomes and analyze the cutaneous molecular changes occurring as a result of surgical intervention. After LaBCC debulking, patients underwent a punch biopsy of residual basal cell carcinoma tissue 1 week later. RT-qPCR analysis of 24 Notch and Wnt signaling-associated genes revealed elevated PTCH1, HEY2, LGR6, FZD2, LEF1, ALCAM, and RUNX1 expressions in follow-up biopsies compared with those in patient-matched debulked tissue. Immunoblot and immunostaining further confirmed elevated Notch signaling in follow-up biopsy tissue compared with that in patient-matched debulked tumor tissue. Patients 1, 3, and 4 displayed a clinical response to debulking followed by vismodegib, whereas patient 2 was lost to follow-up after debulking. These findings suggest that surgical manipulation of LaBCCs is correlated with molecular alterations in signaling pathways associated with cellular reprogramming.

Interference of FZD2 suppresses proliferation, vasculogenic mimicry and stemness in glioma cells via blocking the Notch/NF­κB signaling pathway.

Frizzled family protein 2 (FZD2) is widely associated with tumor development and metastasis. The present study aimed to gain an insight into the role and regulatory mechanism of FZD2 in glioma. The expression level of FZD2 in normal astrocyte and glioma cells was determined by reverse transcription-quantitative PCR and western blotting, and cell transfection was conducted for FZD2 expression knockdown. Malignant behaviors including cell proliferation, migration and invasion, vasculogenic mimicry (VM) and cell stemness were determined using Cell Counting Kit-8, 5-Ethynyl-2'-deoxyuridine (EdU) staining, colony formation, wound healing, Transwell, 3D culturing and sphere formation assays. The expression levels of proteins related to stemness, epithelial-mesenchymal transition (EMT) and Notch/NF-κB signaling were measured by western blotting. Then, the Notch agonist, Jagged-1 (JAG), was adopted for rescue experiments. The results demonstrated that FZD2 was highly expressed in glioma cells. Interference of FZD2 expression suppressed the proliferation of glioma cells, as evidenced by the reduced cell viability and the number of EdU+ cells and colonies. Meanwhile, the reduced sphere formation ability and decreased protein expression of Nanog, Sox2 and Oct4 following FZD2 knockdown confirmed that FZD2 repressed cell stemness in glioma. Additionally, FZD2 knockdown suppressed the migration, invasion, EMT and VM formation capabilities of glioma cells, and also blocked the Notch/NF-κB signaling pathway. Furthermore, activation of Notch by JAG treatment partially reversed the aforementioned FZD2 knockdown-mediated changes in glioma cell malignant behaviors. In conclusion, FZD2 may contribute to glioma progression through activating the Notch/NF-κB signaling pathway, providing a plausible therapeutic target for the treatment of glioma.

Targeting Notch signaling pathways with natural bioactive compounds: a promising approach against cancer.

Notch signaling pathway is activated abnormally in solid and hematological tumors, which perform essential functions in cell differentiation, survival, proliferation, and angiogenesis. The activation of Notch signaling and communication among Notch and other oncogenic pathways heighten malignancy aggressiveness. Thus, targeting Notch signaling offers opportunities for improved survival and reduced disease incidence. Already, most attention has been given to its role in the cancer cells. Recent research shows that natural bioactive compounds can change signaling molecules that are linked to or interact with the Notch pathways. This suggests that there may be a link between Notch activation and the growth of tumors. Here, we sum up the natural bioactive compounds that possess inhibitory effects on human cancers by impeding the Notch pathway and preventing Notch crosstalk with other oncogenic pathways, which provoke further study of these natural products to derive rational therapeutic regimens for the treatment of cancer and develop novel anticancer drugs. This review revealed Notch as a highly challenging but promising target in oncology.

Intracellular pH differentially regulates transcription of metabolic and signaling pathways in normal epithelial cells.

Intracellular pH (pHi) dynamics regulate normal cell function, and dysregulated pHi dynamics is an emerging hallmark of cancer (constitutively increased pHi) and neurodegeneration (constitutively decreased pHi). However, the molecular mechanisms by which pHi dynamics regulate cell biology are poorly understood. Here, we discovered that altering pHi in normal human breast epithelial cells triggers global transcriptional changes. We identified 176 genes differentially regulated by pHi, with pHi-dependent genes clustering in signaling and glycolytic pathways. Using various normal epithelial cell models, we showed pH-dependent Notch1 expression, with increased protein abundance at high pHi. This resulted in pH-dependent downstream signaling, with increased Notch1 signaling at high pHi. We also found that high pHi increased the expression of glycolytic enzymes and regulators of pyruvate fate, including lactate dehydrogenase and pyruvate dehydrogenase kinase. These transcriptional changes were sufficient to alter lactate production, with high pHi shifting these normal epithelial cells toward a glycolytic metabolism and increasing lactate production. Thus, pHi dynamics transcriptionally regulate signaling and metabolic pathways in normal epithelial cells. Our data reveal new molecular regulators of pHi-dependent biology and a role for increased pHi in driving the acquisition of cancer-associated signaling and metabolic changes in normal human epithelial cells.

Uncommon Posterior Disc Displacement of Temporomandibular Joint - A Case Report.

Rationale: Posterior disc displacement (PDD) is an uncommon condition in which disc tissue is located between the posterior surface of the condyle and post-glenoid tubercle. The etiopathogenesis of this condition is idiopathic. There are different predisposing factors in the literature which are consistent with the presented case such as lack of anterior prominence of the disc, thinning of the posterior zone of the disc and perforation of the disc. Patient Concerns: We report an uncommon temporomandibular joint (TMJ) arthropathy case of a 33-year-old female patient, who presented with long-standing TMJ pain associated with limited mouth opening. Diagnosis: The patient was diagnosed with non-reducible PDD of TMJ bilaterally. Treatment: Open surgery of TMJ (Discopexy) was the choice of treatment to release and mobilise discs. Outcomes: A noticeable increase in mouth opening without pain in TMJ area was achieved immediately after surgery and remained stable during periodic follow-ups. Take-away Lessons: The importance of magnetic resonance imaging as a diagnostic tool for arthropathy, to determine the proper management is essential. Moreover, the root of the helix inter tragus notch incision presents an advantage of open surgery of TMJ which results in immediate outcome with limited complications.

Preimplantation Genetic Testing Inhibits the Transmission of Pathogenic Variants Associated With Cerebral White Matter Disease.

Hereditary white matter disease is a series of progressive genetic diseases that mainly affect the white matter of the central nervous system. The development of molecular genetics enables the clinical diagnosis, carrier detection, and prenatal diagnosis of hereditary white matter disease. Here, we block the transmission of pathogenic variants in ABCD1 and NOTCH3 in a family with cerebral white matter disease via preimplantation genetic testing (PGT). Pathogenic genes were identified based on clinical manifestations, genetic background, and the results of targeted gene capture sequencing. A blastocyst biopsy was performed, and multiple annealing and looping-based amplification (MALBAC), next-generation sequencing (NGS), and single nucleotide polymorphism (SNP) arrays were used to analyze ploidy and the state of the gene mutations. The proband (III:1) had hemizygous mutations in ABCD1 (c.323C>A (p.Ser108 *) and c.775C>T (p.Arg259Trp)) and heterozygous mutations in NOTCH3 (c.1630C>T (p.Arg544Cys)), which were maternally inherited (II:2). After genetic analysis, a euploid blastocyst without ABCD1 and NOTCH3 variations was transferred. A healthy male baby was born at full term, and the results of prenatal diagnosis by amniocentesis in the second trimester verified the results of PGT. To our knowledge, this is the first report of simultaneously blocking the transmission of pathogenic variants in ABCD1 and NOTCH3 via PGT. This report highlights the feasibility and effectiveness of PGT in preventing cerebral adrenoleukodystrophy (cALD) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and provides valuable insights for the diagnosis and treatment of similar cases.

Dynamic regulation of innate lymphoid cell development during ontogeny.

The helper-like ILC contains various functional subsets, such as ILC1, ILC2, ILC3 and LTi cells, mediating the immune responses against viruses, parasites, and extracellular bacteria, respectively. Among them, LTi cells are also crucial for the formation of peripheral lymphoid tissues, such as lymph nodes. Our research, along with others', indicates a high proportion of LTi cells in the fetal ILC pool, which significantly decreases after birth. Conversely, the proportion of non-LTi ILCs increases postnatally, corresponding to the need for LTi cells to mediate lymphoid tissue formation during fetal stages and other ILC subsets to combat diverse pathogen infections postnatally. However, the regulatory mechanism for this transition remains unclear. In this study, we observed a preference for fetal ILC progenitors to differentiate into LTi cells, while postnatal bone marrow ILC progenitors preferentially differentiate into non-LTi ILCs. Particularly, this differentiation shift occurs within the first week after birth in mice. Further analysis revealed that adult ILC progenitors exhibit stronger activation of the Notch signaling pathway compared to fetal counterparts, accompanied by elevated Gata3 expression and decreased Rorc expression, leading to a transition from fetal LTi cell-dominant states to adult non-LTi ILC-dominant states. This study suggests that the body can regulate ILC development by modulating the activation level of the Notch signaling pathway, thereby acquiring different ILC subsets to accommodate the varying demands within the body at different developmental stages.

MiR-338-5p, a novel metastasis-related miRNA, inhibits triple-negative breast cancer progression by targeting the ETS1/NOTCH1 axis.

Breast cancer ranks as the most prevalent cancer globally, surpassing lung cancer, with recurrence/metastasis to be its main account for the cancer-related mortality. MicroRNAs (miRNAs) participate critically in various physiological and pathological processes through posttranscriptional regulation of downstream genes. Our preliminary findings identified miR-338-5p, potentially linked to metastasis in breast cancer, a previously unexplored area. Analysis of the GSE38867 dataset revealed the decreased miR-338-5p expression in metastatic breast cancer compared to normal tissues. Cellular function experiments and a xenograft tumor model demonstrated the inhibitory function of miR-338-5p on the progression of breast cancer in vitro and in vivo. Furthermore, it downregulated the expression of mesenchymal biomarkers and NOTCH1 significantly. With the predicting targets of miR-338-5p and transcription factors of the NOTCH1 gene, coupled with dual luciferase reporter assays, it is identified ETS1 as the interactor between miR-338-5p and NOTCH1. In breast cancer tissues, as well as in our xenograft tumor model, expression of ETS1 and NOTCH1 was positively correlated using immunohistochemical staining. This study reports, for the first time, on the miR-338-5p/ETS1/NOTCH1 axis and its pivotal role in breast cancer proliferation and metastasis. These findings propose a novel therapeutic strategy for breast cancer patients and lays a foundation for its clinical detection and treatment evaluation.

The NOTCH1 and miR-34a signaling network is affected by TP53 alterations in CLL.

In chronic lymphocytic leukemia (CLL), TP53 mutations or deletions on chromosome 17p lead to adverse prognosis and reduced levels of miR-34a, which targets NOTCH1. Also, hyperactivated NOTCH1 signaling is crucial for CLL progression. Here we explored the interaction between p53, miR-34a, and NOTCH1 in CLL. We investigated the effect of p53 and miR-34a on NOTCH1 signaling and expression in CLL cells with altered TP53. Our results indicate that miR-34a reduces NOTCH1 3' UTR activity but might not be a mediator between p53 signaling and NOTCH1. p53 activation increases miR-34a expression and NOTCH1 protein levels, correlating with decreased NOTCH1 and miR-34a levels in primary CLL cells with TP53 alterations. Some samples with high NOTCH1 levels presented increased BCL-2, suggesting an anti-apoptotic mechanism of a potentially direct p53-NOTCH1 relation in CLL. This study deepens the understanding of the p53-miR-34a-NOTCH1 signaling network, providing insights that could guide future therapeutic strategies for CLL.

Notch Signaling in Central Nervous System: From Cellular Development to Multiple Sclerosis Disease.

INTRODUCTION/OBJECTIVE: Multiple sclerosis (MS), is characterized by autoimmune-driven neuroinflammation, axonal degeneration, and demyelination. This study aimed to explore the therapeutic potential of targeting Notch signaling within the central nervous system (CNS) in the context of MS. Understanding the intricate roles of Notch signaling could pave the way for targeted interventions to mitigate MS progression. METHODS: A comprehensive literature review was conducted using databases such as PubMed, Web of Science, and Scopus. Keywords such as "Notch signaling," "neuroglial interactions," and "MS" were used. The selection criteria included relevance to neuroglial interactions, peer-reviewed publications, and studies involving animal models of MS. RESULTS: This review highlights the diverse functions of Notch signaling in CNS development, including its regulation of neural stem cell differentiation into neurons, astrocytes, and oligodendrocytes. In the context of MS, Notch signaling has emerged as a promising therapeutic target, exhibiting positive impacts on neuroprotection and remyelination. However, its intricate nature within the CNS necessitates precise modulation for therapeutic efficacy. CONCLUSION: This study provides a comprehensive overview of the potential therapeutic role of Notch signaling in MS. The findings underscore the significance of Notch modulation for neuroprotection and remyelination, emphasizing the need for precision in therapeutic interventions. Further research is imperative to elucidate the specific underlying mechanisms involved, which will provide a foundation for targeted therapeutic strategies for the management of MS and related neurodegenerative disorders.

TMEM252 inhibits epithelial-mesenchymal transition and progression in papillary thyroid carcinoma by regulating Notch1 expression.

BACKGROUND: Papillary thyroid carcinoma (PTC) accounts for about 85% of thyroid cancer cases. Transmembrane protein 252 (TMEM252) is a gene encoding a transmembrane protein that has only been reported to be associated with triple-negative breast cancer. Herein, we first elucidated the physiological roles and possible regulatory proteins of TMEM252 in PTC pathogenesis. METHODS: Quantitative real-time polymerase chain reaction, western blot, and immunohistochemical analyses were utilized to ascertain the relative TMEM252 expression in PTC and surrounding normal tissues. Functional investigations involved CCK-8 viability assay, EdU incorporation assay for proliferation, transwell assays for migration and invasion, and an in vivo tumor development assessment to evaluate the TMEM252-mediated regulation of tumor formation. RESULTS: Our results first revealed diminished TMEM252 transcript and protein expressions in PTC tissues and cell lines. TMEM252 overexpression suppressed cell proliferation through reducing p53, p21, and p16 expression. Conversely, TMEM252 depletion has opposite effects in PTC cells both in vivo. Additionally, the upregulation of TMEM252 demonstrated cell migration and invasion suppression by impeding the epithelial-mesenchymal transition (EMT) process via inhibition of the Notch pathway. Furthermore, overexpression of TMEM252 suppressed tumor growth in vivo. CONCLUSION: Our study elucidates that TMEM252 suppresses PTC progression by modulating the Notch pathway. These findings underscore TMEM252 is a potential therapeutic target in managing PTC.

Prognostic and predictive impact of NOTCH1 in early breast cancer.

PURPOSE: Systemic therapy plays a major part in the cure of patients with early breast cancer (eBC). However, personalized treatment concepts are required to avoid potentially harmful overtreatment. Biomarkers are pivotal for individualized therapy. The Notch signalling pathway is widely considered as a suitable prognostic or predictive marker in eBC. This study aimed primarily at assessing the relationship between NOTCH1 mRNA expression levels and histopathological features of breast cancer tumors, as well as clinical characteristics of the correspondent eBC patients. As a secondary aim, we investigated the prognostic and predictive value of NOTCH1 by assessing possible associations between NOTCH1 mRNA expression and recurrence-free interval (RFI) and overall survival after five years of observation. PATIENTS AND METHODS: The relative NOTCH1 mRNA expression was determined in 414 tumour samples, using quantitative PCR in a prospective, multicenter cohort (Prognostic Assessment in Routine Application (PiA), 2009-2011, NCT01592825) of 1,270 female eBC patients. RESULTS: High NOTCH1 mRNA expression was detected in one-third of the tumours and was associated with negative hormone receptor status and high uPA/PAI-1 status. In addition, high NOTCH1 mRNA expression was found to be associated with more RFI related events (adjusted hazard ratio 2.1, 95% CI 1.077-4.118). Patients who received adjuvant chemotherapy and had high NOTCH1 mRNA expression in the tumour (n = 86) were three times more likely to have an RFI event (adjusted hazard ratio 3.1, 95% CI 1.321-7.245, p = 0.009). CONCLUSION: In this cohort, NOTCH1 mRNA expression had a prognostic and predictive impact. Tumours with high NOTCH1 mRNA expression may be less sensitive to cytotoxic treatment and downregulation of the Notch signalling pathway (e.g. by γ-secretase inhibitors) may be valuable for eBC therapy as an individualised treatment option.

Vasorin (VASN) overexpression promotes pulmonary metastasis and resistance to adjuvant chemotherapy in patients with locally advanced rectal cancer.

BACKGROUND: LARC patients commonly receive adjuvant therapy, however, hidden micrometastases still limit the improvement of OS. This study aims to investigate the impact of VASN in rectal cancer with pulmonary metastasis and understand the underlying molecular mechanisms to guide adjuvant chemotherapy selection. METHODS: Sequencing data from rectal cancer patients with pulmonary metastasis from Sun Yat-sen University Cancer Center (SYSUCC) and publicly available data were meticulously analyzed. The functional role of VASN in pulmonary metastasis was validated in vivo and in vitro. Coimmunoprecipitation (co-IP), immunofluorescence, and rescue experiments were conducted to unravel potential molecular mechanisms of VASN. Moreover, VASN expression levels in tumor samples were examined and analyzed for their correlations with pulmonary metastasis status, tumor stage, adjuvant chemotherapy benefit, and survival outcome. RESULTS: Our study revealed a significant association between high VASN expression and pulmonary metastasis in LARC patients. Experiments in vitro and in vivo demonstrated that VASN could promote the cell proliferation, metastasis, and drug resistance of colorectal cancer. Mechanistically, VASN interacts with the NOTCH1 protein, leading to concurrent activation of the NOTCH and MAPK pathways. Clinically, pulmonary metastasis and advanced tumor stage were observed in 90% of VASN-positive patients and 53.5% of VASN-high patients, respectively, and VASN-high patients had a lower five-year survival rate than VASN-low patients (26.7% vs. 83.7%). Moreover, the Cox analysis and OS analysis indicated that VASN was an independent prognostic factor for OS (HR = 7.4, P value < 0.001) and a predictor of adjuvant therapy efficacy in rectal cancer. CONCLUSIONS: Our study highlights the role of VASN in decreasing drug sensitivity and activating the NOTCH and MAPK pathways, which leads to tumorigenesis and pulmonary metastasis. Both experimental and clinical data support that rectal cancer patients with VASN overexpression detected in biopsies have a higher risk of pulmonary metastasis and adjuvant chemotherapy resistance.

KMT2D mutations promoted tumor progression in diffuse large B-cell lymphoma through altering tumor-induced regulatory T cell trafficking via FBXW7-NOTCH-MYC/TGF-ß1 axis.

Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.

THBS2 promotes gastric cancer progression and stemness via the Notch signaling pathway.

Thrombospondin-2 (THBS2), a secreted extracellular matrix protein, plays a crucial role in various biological processes including angiogenesis, tissue remodeling, and inflammation. Our study focuses on its function in human gastric cancer (GC). Through bioinformatics and tumor tissue analysis, we compared THBS2 expression in GC tissues and adjacent tissues, and predicted regulatory upstream and downstream molecules. The direct regulatory effect of miR-29b-3p on THBS2 was evaluated through dual-luciferase reporter assays, showing that miR-29b-3p targets the 3'-UTR of THBS2 mRNA, reducing its expression in GC cells. The influence of THBS2 on tumorigenesis and stemness was examined on protein expression levels via Western blot. In vivo, THBS2's role was investigated through xenograft and metastasis assays in nude mice, demonstrating that downregulation of THBS2 impairs GC tumorigenesis and liver metastasis. Our study identified THBS2 as a highly expressed prognostic factor in GC patients. Functionally, THBS2 promotes GC progression through the Notch signaling pathway by regulating Notch3, NEY1, and HES1 proteins, and sustains cancer stem cell-like characteristics by Notch3, including the expression of CD44, Nanog, OCT4, and SOX2. In sum, our study reveals that THBS2 promotes GC progression and stemness, modulated negatively by miR-29b-3p. This suggests potential therapeutic targets within the THBS2/Notch signaling axis for combating gastric cancer.

Dynamics of Endothelial Cell Diversity and Plasticity in Health and Disease.

Endothelial cells (ECs) are vital structural units of the cardiovascular system possessing two principal distinctive properties: heterogeneity and plasticity. Endothelial heterogeneity is defined by differences in tissue-specific endothelial phenotypes and their high predisposition to modification along the length of the vascular bed. This aspect of heterogeneity is closely associated with plasticity, the ability of ECs to adapt to environmental cues through the mobilization of genetic, molecular, and structural alterations. The specific endothelial cytoarchitectonics facilitate a quick structural cell reorganization and, furthermore, easy adaptation to the extrinsic and intrinsic environmental stimuli, known as the epigenetic landscape. ECs, as universally distributed and ubiquitous cells of the human body, play a role that extends far beyond their structural function in the cardiovascular system. They play a crucial role in terms of barrier function, cell-to-cell communication, and a myriad of physiological and pathologic processes. These include development, ontogenesis, disease initiation, and progression, as well as growth, regeneration, and repair. Despite substantial progress in the understanding of endothelial cell biology, the role of ECs in healthy conditions and pathologies remains a fascinating area of exploration. This review aims to summarize knowledge and concepts in endothelial biology. It focuses on the development and functional characteristics of endothelial cells in health and pathological conditions, with a particular emphasis on endothelial phenotypic and functional heterogeneity.

A Case of Lateral Meningocele Syndrome without Lateral Meningoceles.

Introduction: Lateral meningocele syndrome (LMS), also known as Lehman syndrome, is caused by pathogenic variants in exon 33 of NOTCH3. Variants in this final exon of NOTCH3 interrupt the regulatory PEST domain, leading to enhanced NOTCH3 signaling due to prolonged cellular half-life. Individuals with LMS are expected to have multiple lateral meningoceles, developmental delay, neonatal hypotonia, dysmorphic facial features, and feeding difficulties. Case Presentation: We report an 8-year-old male with a history of autism, feeding difficulties, developmental delay, severe intellectual disability, and self-injurious behavior. Genetic testing revealed a NOTCH3 c.6663C>G (p.Y2221*) pathogenic variant in exon 33, consistent with a diagnosis of LMS. A follow-up spine MRI showed a ventral sacral extradural arachnoid cyst but no lateral meningoceles. This individual's most recent exam noted multiple dysmorphic features including prominent metopic ridging, broad forehead, downslanting palpebral fissures, high-arched palate, long narrow philtrum, mild pectus excavatum, and wide-based gait. Discussion/Conclusion: This individual shares the dysmorphic facial features, ongoing G-tube dependence, failure to thrive, and developmental delay seen in other individuals with LMS. His lack of lateral meningoceles expands the phenotype for this condition, as all previously reported individuals with molecularly confirmed LMS had multiple lateral meningoceles before age 8 years with an average age of identification at 4 years.